Opioid regulation of hypothalamic neurons

描述(申请人提供)：阿片受体激动剂在产生止痛方面非常有效，但由于神经奖赏回路的激活而导致的耐受性和高滥用倾向的形成阻碍了它们的临床应用。因此，了解阿片类药物如何调节奖赏电路，以及阿片受体信号如何随着阿片类药物的暴露而变化，是克服目前阿片类药物治疗临床局限性的关键步骤。下丘脑前阿片黑素皮质素(POMC)神经元是释放阿片类药物并对其作出反应的一个重要的奖赏通路。最近的数据表明，POMC神经元受作用于POMC神经元的阿片类物质的调节，也受作用于POMC神经元突触前终末的阿片类物质的调节。有趣的是，当POMC神经元上的突触后u阿片受体在几分钟内发生脱敏时，介导递质释放抑制的突触前u阿片受体不容易脱敏。本研究的目的是：1)确定突触前对脱敏反应的机制；2)确定突触前和突触后阿片受体调节的不同结果。这些目标将通过在脑片中使用电生理、光遗传学和成像方法来实现。这些结果可能为预防突触后受体脱敏的方法提供洞察力，并将彻底定义阿片类药物在急性和长期接触阿片类药物时如何通过突触前和突触后受体影响奖赏回路中的神经元活动。

DESCRIPTION (provided by applicant): Opioid receptor agonists are highly effective at producing analgesia, but their clinical use is hindered by the development of tolerance and high abuse liability resulting from activation of the neural reward circuitry. Therefore, understanding how opioids regulate reward circuits and how opioid receptor signaling changes with opioid exposure are key steps towards overcoming current clinical limitations of opioid therapy. One important reward pathway that releases and responds to opioids includes the hypothalamic proopiomelanocortin (POMC) neurons. Recent data show that POMC neurons are regulated by opioids acting on POMC neurons and also by opioids acting on terminals presynaptic to POMC neurons. Interestingly, while postsynaptic mu opioid receptors on POMC neurons undergo desensitization within minutes, presynaptic mu opioid receptors that mediate the inhibition of transmitter release do not readily desensitize. The goals of the present proposal are to 1) determine the mechanisms underlying the presynaptic resistance to desensitization and 2) to determine the consequence of differential pre- and postsynaptic opioid receptor regulation. These goals will be achieved using electrophysiologic, optogenetic and imaging approaches in brain slices. The results may provide insight into ways to prevent postsynaptic receptor desensitization and will thoroughly define how opioids affect neuron activity in a reward circuit via pre- and postsynaptic receptors during acute and chronic exposure to opioids.